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What caused this 58-year-old heroin user to suddenly develop jaundice and malaise? That's the diagnostic challenge faced by Brian Pearlman, MD, of Emory School of Medicine in Atlanta, writing in .

The patient presented to the emergency department after suddenly developing yellowing of the skin and sclera – she told clinicians she had been feeling poorly for the past 8 days. She had a history of intravenous heroin use, and had been diagnosed with chronic inactive hepatitis B virus (HBV) infection, but was not receiving any treatment.

Lab tests showed her serum HBV DNA value was low, her liver enzyme values were normal, and there was no evidence of liver cirrhosis. She said she had last injected heroin 9 days previously, was not taking prescription medications or herbal treatments, had not traveled outside the U.S., and had not eaten any raw meat.

Her vital signs were normal, as were signs of her mental activity; results of a physical examination were also normal except for the scleral icterus.

Blood tests were negative for hepatitis C virus RNA, anti–hepatitis A immunoglobulin (Ig)M, and HIV antibody. Her medical history showed that results of a liver ultrasound from 6 months previously were normal, as was the repeat liver ultrasound with Doppler that had been performed when she was admitted to the ER.

Among other laboratory test findings:

• Total bilirubin: 7.3 mg/dL (reference range 0.0-1.0 mg/dL)

• Alanine aminotransferase (ALT): 1,269 U/L (reference range 10-55 U/L)

• Aspartate aminotransferase (AST): 945 U/L (reference range 10-40 U/L)

Clinicians considered various causes for the patient's sudden-onset jaundice and recent increase in ALT, AST, and bilirubin levels, including autoimmune hepatitis, HIV, and hepatitis E. The team decided that based on her intravenous drug use and chronic HBV infection, the symptoms were unlikely to be due to autoimmune hepatitis. HIV was also ruled out, since it would not typically cause this degree of increase in the levels. Hepatitis E was also ruled out because the patient had neither traveled outside the U.S. nor consumed raw meat.

The attending clinician decided that hepatitis D superinfection was the probable cause of the sudden-onset jaundice and newly elevated ALT, AST, and bilirubin. The next step was to order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, to test for HDV RNA.

The blood test results for HDV were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The medical team's correct diagnosis of HDV was based on recognition that in the absence of acute infection with hepatitis A or C, HDV was the most likely cause of the symptoms in a patient who uses intravenous drugs and has chronic HBV infection.

The patient declined the standard recommended treatment with pegylated interferon alfa, and within 8 weeks, she reported feeling better and her scleral icterus had cleared up.

At the patient's most recent follow-up assessment, about 6 months after her initial presentation to the clinic, repeat lab tests showed that her total serum bilirubin had returned to normal (0.6 mg/dL), she had mildly elevated ALT (48 U/L), low HBV DNA (1,350 IU/mL), and high serum HDV RNA (880,000 IU/mL), reflecting chronic HDV infection, Pearlman said.

The patient was advised to return twice yearly for liver ultrasound monitoring for hepatocellular carcinoma, and she has begun participating in an outpatient drug rehabilitation program.

Discussion

Pearlman explained that patients infected with HDV typically have simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV. This is because HDV – the smallest virus known to infect humans – consists of single-stranded, circular RNA, and is defective, "because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission," he wrote.

Although clinically, HDV and acute HBV infections present with the same symptoms and characteristics, HDV infection carries a higher risk of acute liver failure, particularly for intravenous drug users, the author noted.

In the majority of patients (about 90-95%), acute HDV-HBV co-infection resolves on its own. However, HDV that occurs as a superinfection generally becomes chronic – i.e., persisting for longer than 6 months – and typically is associated with a more severe course of illness.

Once HDV infection becomes chronic, it is considered to be the most severe form of viral hepatitis, with progression to cirrhosis in 10–15% of patients within 2 years. And in about 70-80% of patients, long-term HDV-HBV co-infection will advance and lead to cirrhosis within 5 to 10 years after diagnosis -- "compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma," Pearlman said.

He noted that HDV infection is estimated to affect 62-72 million people worldwide, and although the incidence varies regionally, it still represents almost 1% of the global population. The virus is most commonly found in Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil, and data suggest a 13% to 14.6% in a pooled population of carriers of the virus. IV drug users accounted for over one-third of cases, and an additional 17% were associated with high-risk sexual behavior, Pearlman noted.

Although there have to date been no large controlled trials to assess the effects of screening for HDV infection, the American Association for the Study of Liver Diseases currently recommends hepatitis B surface antigen (HBsAg)-positive individuals who have at least one of the following risk factors:

• HIV

• Intravenous drug use

• Are men who have sex with men

• Are at risk for sexually transmitted diseases

• Are immigrants from areas of high HDV endemicity

Screening for HDV should also be considered in the presence of elevated ALT levels and low HBV DNA levels, Pearlman said. "Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection."

"The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level," he continued. "Unfortunately, only about 25% to 30% of patients achieve a sustained response, in which serum HDV RNA level is undetectable after completing half the course of treatment, and is common."

Liver transplantation may be an option for patients with chronic HDV infection and acute deterioration of liver function, Pearlman noted, adding that recent "treatment targets include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes."

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